Process for preparing N-[1-(S)-ethyoxycarbonyl-3-phenylpropyl]-L-ananine N-carboxyanhydride

ABSTRACT

A process for preparing N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride of the following formula (I),is to react N-[1-(S)-ethyoxy carbonyl-3-phenylpropyl]-L-alanine with XCOOR, wherein X is halogen atom, R is C1-C6 alkyl, to obtain a N-alkoxycarbonyl compound, then reacting with an acyl group activation reagent, finally contact with water. The compound of formula (I) is a key intermediate of ACE inhibitors.

This application is a divisional application of U.S. application Ser.No. 09/689,667, filed Oct. 13, 2000, now U.S. Pat. No. 6,262,274 ofwhich the entire disclosure of the pending, prior application is herebyincorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for preparing the prodrug ofangiotensin converting enzyme (hereinafter referred to as “ACE”)inhibitors. More particularly, it relates to a process for preparingN-[1-(S)-ethyoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride(hereinafter referred to as “NEPA-NCA”).

2. Description of the Prior Art

Enalapril Maleate of the following, formula (II)

which is a well-known antihypertensive agent due to an excellent ACEinhibitory activity. EP215335 discloses a process for preparing theformula (II) by using the NEPA-NCA of the formula (I) as startingmaterial which undergo condensation reaction with L-proline under thebasic condition to obtain theN-[1-(S)-ethyoxycarbonyl-3-phenylpropyl]-L-alanine (hereinafter referredto as “Enalapril”):

After adding maleic acid, an amino acid salt as the formula (II) canthus be obtained.

Using NEPA-NCA to react with the different amino acids in similarcondensation reactions can obtain the different ACE inhibitors, forexample, Ramipril, Trandolapril, Delapril, Imidapril and Quinapril-HCl.

The processes for preparing NEPA-NCA of the formula (I) are to reactN-[1-(S)-ethyoxy carbonyl-3-phenylpropyl]-L-alanine (hereinafterreferred as to “NEPA”) of the following formula (III)

with phosgene, diphosgene or triphosgene. Those methods are well knownand are disclosed in JP57175152A, U.S. Pat. No. 4,496,541 and EP215335.Although the yield of the above phosgene method is relatively high, itis needed to use toxic phosgene in process. As for the purpose ofindustrial production, there should be a special design for avoidingfrom the leakage of phosgene, as critical control point for safetycontrol of hazards. Although diphosgene or triphosgene is liquid orsolid form at room temperature, however it produces toxic vapor when beheated. Furthermore, the effluents produced by those processes are alsopollutive.

U.S. Pat. No. 5,359,086 discloses a non-phosgene method which usingN,N′-carbonyldiimidazole instead of phosgene. HoweverN,N′-carbonyldiimidazole is relatively expensive and needs to usephosgene for recovery.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a method to prepareNEPA-NCA without using noxious phosgene, diphosgene or triphosgene.

It is another object of the present invention to provide an economical,safe, simple process of the industrial production of NEPA-NCA.

In accordance with the invention, then, a process is provided forsynthesizing NEPA-NCA of the following formula (I),

which comprises reacting NEPA of the following formula (III)

with XCOOR of the following formula (V),

XCOOR  (V)

wherein X is halogen atom, R is C₁-C₆ alkyl, to form a N-alkoxycarbonylcompound, then react with an acyl group activation reagent, and finallyreact with water.

The method of the present invention can use the different amino acids asstarting materials to prepare the different N-carboxyanhydridecompounds. Examples of the different amino acids are:

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The process of the present invention is shown by the following reactionscheme,

wherein X is halogen atom, R is C₁-C₆ alkyl.

As shown by the above reaction scheme, NEPA of the formula (III) isreacted with the compound of formula (V) in the presence of organicsolvent to form an N-alkoxycarbonyl compound of formula (IV). Then thecompound of formula (IV) is reacted with an acyl group activationreagent, and finally contacted with water to obtain the compound offormula (I).

The organic solvents for the reaction can be aprotic solvents, forexamples: dichloromethane, dichloroethane, toluene, ethylacetate,hexane, cyclohexane or heptane. It is preferred that said aproticsolvents are dichloromethane, dichloroethane, or toluene, and morepreferably is dichloroethane.

It is preferred that the halogen atoms of formula (V) compound arechlorine atom, bromine atom or iodine atom, and more preferably ischlorine atom. Typically, R is, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, or hexyl, andmore preferably R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,or tert-butyl.

The acyl group activation reagent can be acyl chlorination reagent (forexample: thionyl chloride or phosphorus pentachloride), acid anhydrideor acyl halogen (for example: acetyl chloride), and more preferably isthionyl chloride, acetic anhydride or acetyl chloride.

When NEPA is reacted with formula (V) compound, the reaction temperatureis not strictly limited. The range of the reaction temperature can befrom 25° C. to 120° C., it depends on what kind of organic solvents usedin the reaction. The reaction time is also not strictly limited, andmore preferably is 0.45 to 3.0 hours. When N-alkoxycarbonyl compound offormula (IV) is reacted with the acyl group activation reagent, thereaction temperature and the reaction time are depended on what kind ofreagents chosen in the reaction. Generally speaking, the reactiontemperature is ranged from −10° C. to 120° C. and the reaction time is 2to 14 hours.

The method of the present invention provides advantages of non-toxic,safety and easy to handle process.

More detailed examples are used to illustrate the present invention, andthese examples are used to explain the present invention. The examplesbelow, which are given simply by way of illustration, must not be takento limit the scope of the invention. In these examples, parts is countedas weight, temperature is Celsius ° C.

EXAMPLE 1

NEPA (27.9 g), dichloroethane (9 ml), ethyl chloroformate (13.1 g) andtriethylamine (10 g) were added to a reactor equipped with a mechanicalstirrer. The mixture was stirred at room temperature until the reactionwas completed. The organic layer was washed with water (2×50 ml) and wasadjusted to pH 3-4 by adding HCl. The above organic layer was dried withmagnesium sulphate, then filtrated.

Thionyl chloride (13.1 g) was added to a reactor, and the above filtratewas slowly dropped into the reactor at 5˜10° C. The mixture was stirredat room temperature until the reaction was completed. The organic layerwas washed with water (2×50 ml), dried with magnesium sulphate, thenconcentrated to obtain the crude product. The crude product wasrecrystallized to get a white crystalline ofN-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride,yield=70%, mp=68° C.

¹H-NMR(CDCl₃): δ1.26(t, 3H), δ1.53(d, 3H), δ2.22˜2.48(m, 2H),δ2.66˜2.84(m, 2H), δ3.39(q, 1H), δ4.20(d, 2H), δ4.33(d, 1H), andδ7.15˜7.34(m, 5H).

EXAMPLE 2

NEPA (27.9 g), dichloroethane (60 ml), ethyl chloroformate (13.1 g) andpolyvinylpyridine (9.6 g) were added to a reactor equipped with amechanical stirrer. The mixture was stirred at room temperature untilthe reaction was completed. The organic layer was washed with water(2×50 ml) and was adjusted to pH 3-4 by adding HCl. The above organiclayer was dried with magnesium sulphate, then filtrated.

Acetyl chloride (10.2 g) was added to a reactor, and the above filtratewas slowly dropped into the reactor at 5˜10° C. The mixture was stirredat room temperature until the reaction was completed. The organic layerwas washed with water (2×50 ml), dried with magnesium sulphate, thenconcentrated to obtain the crude product. The crude product wasrecrystallized to get a white crystalline ofN-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride,yield=91%, mp=68° C.

EXAMPLE 3

NEPA (560 g), dichloroethane (1200 ml) and ethyl chloroformate (237.6 g)were added to a reactor equipped with a mechanical stirrer. Afterstirred for 0.5 hour, 10M NaOH (230 ml) was added to the reactor. Themixture was stirred for 1 hour.

After the reaction was completed, acetyl chloride (188.4 g) was added tothe reactor. The mixture was stirred for 2 hours at 85˜95° C. Water (800ml) was added to the reactor and the mixture was stirred at 70˜80° C.until the reaction was completed. The organic layer was separated andconcentrated to obtain the crude product. The crude product wasrecrystallized to get a white crystalline ofN-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride,yield=82%, mp=68° C.

EXAMPLE 4

NEPA (27.9 g), toluene (60 ml), and ethyl chloroformate (13.1 g) wereadded to a reactor equipped with a mechanical stirrer. After stirred for1.0 hour, thionyl chloride (12.6 g) was added to the reactor at roomtemperature. The mixture was stirred until the reaction was completed.The organic layer was washed with water (2×50 ml), dried with magnesiumsulphate, then concentrated to obtain the crude product. The crudeproduct was recrystallized to get a white crystalline ofN-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanine N-carboxyanhydride,yield=53%, mp=68° C.

EXAMPLE 5

NEPA (27.9 g), dichloroethane (90 ml), and ethyl chloroformate (13.1 g)were added to a reactor equipped with mechanical stirrer. After stirredfor 1.0 hour, 10M NaOH (10 ml) was added to the reactor. The mixture wasstirred for 0.5 hour.

Upon completion of the reaction, acetic anhydride (5.1 g) was added tothe mixture. After the salt was removed, thionyl chloride (13.1 g) wasadded to the reactor. The mixture was stirred at room temperature untilthe reaction was completed. The organic layer was washed with water (20ml), dried with magnesium sulphate, then concentrated to obtain thecrude product. The crude product was recrystallized to get a whitecrystalline of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl]-L-alanineN-carboxyanhydride, yield=63%, mp=68° C.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the scope thereof, can make various changes andmodifications of the invention to adapt it to various usages andconditions. Thus, other embodiments are also within the claims.

What is claimed is:
 1. A compound of the following formula (IV):

wherein R is C₁-C₆ alkyl.
 2. The compound of claim 1, wherein R ismethyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
 3. Thecompound of claim 1, wherein R is ethyl.